Many genes have been identified that may play a role in increasing individual susceptibility to obesity. Reduced dopamine function appears to play a role in dysfunctional eating patterns and may predispose some individuals to obesity. The long version of the D4 dopamine receptor gene (D4DR) has been shown to alter receptor function and reduce intracellular response to dopamine. It also has been associated with novelty-seeking-related personality traits that are found with greater frequency in obese individuals. We examined the association between the long alleles of the D4DR and obesity in a sample of 115 obese patients participating in a weight management program. No direct relationship was found between the D4DR and body mass or novelty-seeking-related personality traits. We constructed four models of increased obesity risk that included combinations of traditional risk factors (i.e., long-term history of obesity, parental obesity, a body mass index > 40) and elevations on the novelty-seeking-related scales of the Karolinska Scales of Personality. There was a significant increase in the frequency of the D4DR long alleles in individuals defined as high risk using the combination of novelty-seeking-related personality traits, severe obesity (i.e., BMI > 40), and any other traditional risk factor, but not with the traditional risk factors alone. These preliminary data suggest a potential role for the D4DR gene in increasing obesity susceptibility.